Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration

Abstract

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease that was originally discovered in the population from the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region in Quebec. Although the disease progression of ARSACS may start in early childhood, cases with later onset have also been observed. Spasticity and ataxia could be common phenotypes, and retinal optic nerve hypermyelination is detected in the majority of patients. Other symptoms, such as pes cavus, ataxia and limb deformities, are also frequently observed in affected individuals. More than 200 mutations have been discovered in the SACS gene around the world. Besides French Canadians, SACS genetics have been extensively studied in Tunisia or Japan. Recently, emerging studies discovered SACS mutations in several other countries. SACS mutations could be associated with pathogenicity either in the homozygous or compound heterozygous stages. Sacsin has been confirmed to be involved in chaperon activities, controlling the microtubule balance or cell migration. Additionally, sacsin may also play a crucial role in regulating the mitochondrial functions. Through these mechanisms, it may share common mechanisms with other neurodegenerative diseases. Further studies are needed to define the exact functions of sacsin. This review introduces the genetic mutations discovered in the SACS gene and discusses its pathomechanisms and its possible involvement in other neurodegenerative diseases.

Autophagic lysosome reformation in health and disease

“… 270550 604490 SACS sacsin molecular chaperone Required for the formation of autolysosome reformation tubules, via regulation of microtubule dynamics and/or by binding to membrane-deforming effectors including the AP-2-clathrin complex and KIF5B. [ 72 , 73 , 74 , 75 ] Musculardystrophy Predominant-ly skeletal muscle, but can affect other systems. Skeletal muscle degeneration/wasting, loss of ambulation, cardiomyopathy, seizures, cognitive impairment, intellectual disability, microcephaly, short stature, cataracts, neurobehavioral issues.…”

Autophagy and neurodegeneration: Unraveling the role of C9ORF72 in the regulation of autophagy and its relationship to ALS-FTD pathology

“…Likewise, ALR dysfunction is causally implicated in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a fatal, neurodegenerative disorder, wherein cerebellar Purkinje cells selectively degenerate, leading to spasticity and ataxia ( Bagaria et al, 2022 ; Francis et al, 2022 ). ARSACS is caused by mutations in the gene of sacsin molecular chaperone (SACS), leading to a loss of function phenotype.…”

In Vitro Characterization of Motor Neurons and Purkinje Cells Differentiated from Induced Pluripotent Stem Cells Generated from Patients with Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

“…Different causative mutations in the SACS gene are linked to the disease. To date, more than 200 mutations have been identified in this gene [ 5 ]. The SACS gene encodes the protein sacsin, highly expressed in Purkinje cells and motor neurons (MNs), which is involved in molecular chaperoning, mitochondrial transport and integrity, and neurofilament assembly [ 6 ].…”